Identification of SENP1 inhibitors through in silico screening and rational drug design

• Eleven new scaffolds as SENP1 inhibitors discovered through in silico screening.
• New SENP1 inhibitors synthesized and a preliminary SAR discussed.
• Compound 13m showed an IC50 as low as 3.5 μM.

The small ubiquitin-related modifier (SUMO)-specific proteases (SENPs) catalyze the deconjugation of SUMO from their substrate proteins. SENP1 which is the most studied isoform is closely related to many cancers such as prostate cancer and colon cancer, thus representing a potential therapeutic target for cancer treatment. In the present study, we identified eleven SENP1 inhibitors representing a variety of scaffolds through in silico screening. Based on these scaffolds, a series of new compounds were designed and synthesized in order to improve their SENP1 inhibitory potency. As a result, compounds with IC50 as low as 3.5 μM (compound 13m) were obtained and a preliminary structure-activity relationship was discussed.

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